tbuckley/cabot-search huggingface dataset:
Abstract 13336: Rasa3 Affects Key Proliferation and Angiogenic Pathways in and Around Pulmonary Artery Endothelial Cells
Authors: Clare C Prohaska, Yang Bai, Marta T Gomes, Angelia Lockett, Roberto F Machado
Journal: Circulation (2022)

Introduction: Despite improvements in quality of life and functional status, pulmonary hypertension (PH) remains a highly morbid disease with poor life expectancy with no targeted treatments available. RASA3 is a ubiquitously expressed GTPase activating protein that is integral to angiogenesis and barrier function in endothelial cells (EC). In this study, we sought to explore the differential expression of RASA3 in response to PH-relevant stimuli and downstream markers of EC health when RASA3 expression is lost. Methods: Human pulmonary artery cells (PAECs) from Lonza were grown in culture and treated with 1% hypoxia, increasing concentrations of TNF-α for 24 hours or IL-1β for 48 hours and then harvested. Cells were transfected with siRNA directed against RASA3 or non-targeting control and harvested to evaluate downstream markers of EC health, or plated on Matrigel to evaluate angiogenic capabilities. Non-contact co-culture experiments were performed using human pulmonary artery smooth muscle cells (PASMC) with PAECs that were transfected with siRNA against RASA3 or non-targeting control. Results: We found that when untreated PAECs were exposed to 1% hypoxia for up to 96 hours, RASA3 expression was significantly decreased (p=0.046). When treated with increasing concentrations of TNF-α for 24 hours, RASA3 expression decreased (p=0.0002). When PAECs were treated with IL-1β 10ng/mL for 48 hours, RASA3 expression significantly increased (p=0.001). Silenced RASA3 PAECs had significantly less PCNA (p=0.0474), a trend towards increased HIF-2α expression (p=0.08) and increased VEGFR2 expression (p=0.0878). Cells that had silenced RASA3 expression when plated on Matrigel were significantly less able to form rings compared to non-targeting control (p=0.0152). PASMCs that had been co-cultured with silenced RASA3 had significantly increased PCNA compared to PASMCs co-cultured with non-targeting control PAECs (p=0.0467). Conclusions: RASA3 is essential to PAEC homeostasis, and loss of RASA3 affects endothelial cell health as well as affects its local environment. Further studies are ongoing to determine how loss of RASA3 contributes to the development of PH.
Abstract 13386: The Association of High Polygenic Risk With Future Coronary Heart Disease Events Diminishes Later in Life
Authors: Ozan Dikilitas, Johanna Smith, Daniel J Schaid, Iftikhar J Kullo
Journal: Circulation (2022)

Introduction: Polygenic risk scores (PRS) for coronary heart disease (CHD) are associated with incident CHD events. We assessed whether the strength of this association differs over the life course. Methods: We studied 7,958 genotyped participants of European-ancestry without CHD enrolled in the Atherosclerosis Risk in Communities Study (ARIC). Participants were 45-64 years old at the baseline visit occurring 1987-89 with follow up available through 2015. A genome-wide PRS for CHD composed of 1.7 million variants was computed for each participant. Incident CHD was defined as clinically adjudicated myocardial infarction including silent infarction, coronary revascularization, or fatal coronary event. An extended Cox model was constructed with age as the model time scale. The association of PRS with incident CHD was assumed to be log-linear and further modeled as a function of age assuming differing piecewise constant effect sizes across the intervals ≤55, 55-65, 65-80, and ≥80 years. The regression model also included the following covariates: sex, systolic blood pressure, total and HDL cholesterol, history of diabetes, antihypertensive medication use, and smoking status. Results: In the ARIC cohort (median enrollment age 54, interquartile range [IQR] 49-59, female 52%), over a median of 24.5 years (IQR 14.4-28.1), there were 1,872 incident CHD events. In comparison to average polygenic risk for CHD (50th percentile of PRS distribution), harboring high polygenic risk (95th percentile) was associated with a 2.9-fold increased risk of incident CHD (95% CI 2.12-3.95) up to age 55 years, independent of conventional risk factors. The strength of association was attenuated later in life (Hazard ratio, age 55-65, 2.5 [2.14-2.84]; age 65-80, 1.87 [1.68-2.07]; age ≥80, 1.78 [1.38-2.31]) Conclusions: A genome-wide PRS for CHD is more strongly associated with incident coronary events at younger age. The strength of association declined later in life while remaining significant. The age-dependent association of PRS with CHD may need to be accounted for in risk prediction models.
Abstract 12859: Transcatheter Aortic Valve Implants Using Virtual Reality May Predict Paravalvular Leak in Bicuspid Severe Aortic Valve Stenosis
Authors: Johnny Chahine, Demetris Yannopoulos, Ganesh Raveendran, Sergey Gurevich
Journal: Circulation (2022)

Introduction: Preoperative 3-dimensional (3D) planning in transcatheter aortic valve replacement (TAVR) has improved outcomes and reduced adverse events. Moderate and even mild paravalvular leak (PVL) is an important predictor of adverse events. PVL remains a challenge for TAVR in bicuspid severe aortic valve stenosis (AS). Here, we investigate virtual reality (VR) simulated TAVR implants in bicuspid severe AS to predict PVL. Hypothesis: VR TAVR simulation may predict PVL in bicuspid severe AS and allow for improved valve selection before TAVR procedures. Methods: Patients with bicuspid severe AS treated with TAVR between 2014 and 2018 were included. The aortic root, ascending aorta, and left ventricular outflow tract were reconstructed based on pre-operative computed tomography. A 3D TAVR valve was then inserted into the reconstructed root in VR. The primary endpoint was the percent circumference of valve malapposition in VR (Elucis, Realize Medical) as compared to the severity of PVL on postprocedure echocardiography. Results: 12 patients were included in this study. The mean age was 69.2 years ± 17 and 41.7% were female. 75% received a 26mm Sapien 3 valve (Edwards Lifesciences) and 25% had a 29 mm Evolut R CoreValve (Medtronic) implanted. Among patients who had no or trivial PVL (n=9), 7 patients had no malapposition on VR and 2 patients had less than 5% malapposition. Both patients with mild PVL had 10% malapposition. The only patient with moderate PVL had 25% malapposition (table 1, figure 1). There was 100% agreement between the VR simulated implants and post-procedure PVL measured by echocardiography. Conclusion: TAVR implantation in VR may predict PVL in bicuspid severe AS.
Abstract 13846: Shared Curriculum Delivery Gaps Among Advanced Heart Failure and Transplant Cardiology Fellowship Programs
Authors: Michael H Beasley, Donna Windish
Journal: Circulation (2022)

Introduction: Nearly 4,000 heart transplants and more than 5,000 LVAD implants were performed in the US in 2021. Medical care for these patients is performed by Advanced Heart Failure and Transplant Cardiology (AHFTC) physicians. Variations in faculty expertise and patient pathology exist between training programs, and some may be unable to provide a curriculum addressing all recommended competencies during the one-year-long fellowship. This study is a targeted needs assessment identifying gaps in curriculum delivery among US AHFTC fellowship programs. Methods: 50 medical knowledge competencies were selected from the 2017 ACC/AHA/HFSA/ISHLT/ACP Training Statement on Advanced Heart Failure and Transplant Cardiology. AHFTC fellowship programs were identified using the AMA’s FREIDA website. A survey was published on Qualtrics. An anonymous link was emailed to all program directors (PDs), while PDs and program coordinators (PCs) were asked to help distribute the survey to current fellows. Results: 17 PDs and 11 fellows completed the survey. The most common areas where little to no training was reported to be provided were: role of lung transplantation in patients with pulmonary arterial hypertension (68%), pathophysiology of cardiac dysfunction associated with portal hypertension (61%), and conditions that may impact mechanical circulatory support strategies in adult patients with congenital heart disease (58%). Respondents most requested a moderate to a significant amount of more training in the following areas: appropriate treatment of patients with each type of pulmonary hypertension (63%), pharmacology of medications available to treat pulmonary arterial hypertension (58%), and role of lung transplantation in patients with pulmonary arterial hypertension (53%). (The information reported is as of June 12, 2022. Data collection is ongoing.) Conclusions: Common gaps in curriculum delivery among US AHFTC fellowship programs appear to exist. The most desired area for additional instruction involves different aspects of the management of pulmonary hypertension. A focused centralized curriculum could be developed to teach these concepts, thereby better preparing AHFTC fellows to care for these types of patients in the future.
Abstract 14791: Evaluation of Cardiac Size, Shape and Function in Fetuses With Coarctation of the Aorta by Fetal Heart Quantitative Technique
Authors: Juanjuan Liu, Haiyan Cao, Liu Hong, Li Zhang, Mingxing Xie
Journal: Circulation (2022)

Introduction: This study aimed to evaluate the size and shape of the four-chamber view (4CV) and right and left ventricles (RV and LV) as well as the function of the RV and LV in fetuses with coarctation of the aorta (CoA) using fetal heart quantitative (Fetal HQ) technique. Methods: A total of 67 CoA fetuses and 67 gestational age-matched controls were included. Fetal HQ technique was used to obtain the 4CV end-diastolic (ED) width, length, area, and global sphericity index (GSI), RV and LV 24-segment ED diameter (EDD), 24-segment sphericity index (SI), area, and the following functional parameters: (1) fractional area change (FAC); (2) global longitudinal strain (GLS); (3) 24-segment transverse fractional shortening (FS); (4) LV ejection fraction (LVEF), LV ED volume (LVEDV), LV stroke volume (LVSV) and LV output (LVO). Results: Compared with normal controls, the Z-score of 4CV ED width was increased ( P &lt; 0.05), while the GSI was decreased ( P &lt; 0.05) in fetuses with CoA. However, there were no significant differences in the Z-scores of 4CV ED length and area between two groups (both P &gt; 0.05) The RV 24-segment EDD Z-scores, RV area Z-score as well as the RV/LV 24-segment EDD were significantly higher in CoA fetuses than in controls (all P &lt; 0.05). In contrast, the LV 24-segment EDD Z-scores and area Z-score were significantly lower in fetuses with CoA ( P &lt; 0.05). The 24-segment SIs of the LV were significantly higher, while the 24-segment SIs of the RV were significantly lower in CoA group (all P &lt; 0.05). CoA fetuses presented lower GLS, FAC and 24-segment FSs for both RV and LV when compared with normal controls (all P &lt; 0.05). In addition, LVEF, LVEDV Z-score, LVSV Z-score and LVO Z-score were all decreased in CoA fetuses (all P &lt; 0.05). Conclusions: In fetuses with CoA, the 4CV was increased in width and spherical in shape. The LV area and width were decreased, while the transverse width and area of RV was increased. Abnormal SIs reflected a flatter LV and a more spherical RV. RV and LV global, longitudinal, and transverse contractility were all depressed. Fetal HQ can be used to quantitatively analyze cardiac size, shape and function in CoA fetuses, which may improve prenatal diagnosis of CoA.
Abstract 12908: Primary Partners Provide Key Social Support for the Management of Cardiometabolic Disorders in Sub-Saharan Africa
Authors: Allison Ruark, Julie T Bidwell, Rita Butterfield, Torsten Neilands, Sheri Weiser, Nancy Mulauzi, James Mkandawire, Jacqueline Huwa, Amy Conroy
Journal: Circulation (2022)

Introduction: Social support from primary partners has wide-ranging impacts on disease management and health outcomes, although scant research has explored this topic for couples living with cardiometabolic disorders (CMD) in low-resource settings in sub-Saharan Africa. Objectives: To explore patterns of partner support around CMD in Malawian couples Methods: We conducted a qualitative study with 25 married couples in Malawi who had at least one partner with HIV and CMD (either hypertension or diabetes). Index patients were recruited from three HIV care clinics and primary partners were subsequently enrolled. We conducted semi-structured interviews with both partners to understand how couples cope together with CMD and offer social support. Data were coded for patterns and themes within couples and between couples and data matrices were used to summarize the findings. Results: Couples described three patterns of partner support. Instrumental support was provided by partners who offered money for medication, transportation to medical appointments, and healthy foods. Partners also provided reminders to take medication and attend medical appointments, accompanied patients to medical appointments, and monitored medication use. While household chores are typically women’s work, in some cases male partners helped with these activities when their wives were too ill or were experiencing what they believed were symptoms of CMD. Emotional support was provided by partners through encouragement to practice a healthy lifestyle (such as increasing physical activity and reducing salt intake), rest, and reduce stress and avoid arguing. Informational support was provided by partners who gave advice for successful management of CMD and in making health-related decisions such as food purchases. Conclusions: Social support from primary partners around disease management may partially ameliorate inadequate health services for people with CMD in sub-Saharan Africa. While there remains a need to fortify health systems and address barriers to accessing treatment, couple relationships could be leveraged in care services to provide key forms of social support.
Abstract 13651: Adipose Tissue Resolvin Biosynthesis is Abrogated by High Fat Diet-Induced Adrenergic Deficiency
Authors: Jason Hellmann, Ernesto H Pena Calderin, Will G Lynch, Jing-Juan Zheng, Brian E Sansbury, Matthew R Spite, Aruni Bhatnagar, Bradford G Hill
Journal: Circulation (2022)

Diet-induced chronic inflammation in adipose tissue (AT) is associated with systemic insulin resistance. Conversely, exercise (Exe) protects against the development of chronic inflammation and insulin resistance. Our lab recently showed that exercise promotes inflammation resolution through adrenergic stimulation of specialized proresolving mediators (SPMs). In this study, we sought to determine if the proresolving benefits of exercise were dietary dependent. When compared with sedentary controls (Sed), mice exposed to 4 wk of Exe display elevated AT expression of SPM biosynthetic enzyme Alox15 (Sed 1.12±0.18 vs. Exe 1.68±0.13 relative expression, n =5-7), SPM levels (Sed vs. Exe; RvD1 156.7±12.02 vs. 223.0±24.71; 17 R -RvD1 354.0±35.86 vs. 534.4±98.92; RvD4 31.31±6.93 vs. 123.1±30.69; and 17 R -RvD3 2.92±1.08 vs. 8.20±1.70 pg/g, n =5-7), and anti-inflammatory macrophages (F4/80 + CD301 + ; Sed 17.5±3.2 vs. Exe 40.9±4.5 %F4/80 + , n =4-6). These changes were dependent upon diet as short duration feeding with high fat diet (60% kcal from fat; HFD) abrogated the proresolving effect of exercise when compared with low fat diet (10% kcal from fat; LFD) controls. Interestingly, exercise-induced epinephrine (Epi) production in LFD-fed mice (Sed 147.2±24.4 vs Exe 312.5±60.9 ng/mL) was inhibited by HFD (Sed 121.1±22.7 vs. Exe 140.0±16.8 ng/mL). HFD feeding resulted in diminished expression of the Epi biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands when compared with LFD fed animals (protein expression: LFD 1.0±0.25 vs. HFD 0.36±0.15, n =4). These results suggest that the proresolving effects of exercise in adipose tissue are dietary and adrenergic dependent.
Abstract 13856: Ventricular Remodeling and the Effect of Continuous Positive Airway Pressure in Patients With Combined Diabetes Mellitus and Obstructive Sleep Apnea: A Secondary Analysis of a Randomized Clinical Trial
Authors: Thiago Q Silva, Jessie Bakker, Dimitrios Baltzis, Raymond H Chan, Warren J Manning, Meredith Wallace, Carlos A Gongora, Hannah Gilman, Supraja Sama, Sofia Nikolaidou, Andrei Sposito, Otavio R Coelho-filho, Margo Hudson, Michael Jerosch-Herold, Aristidis Veves, Atul Malhotra, Sanjay Patel, Tomas G Neilan
Journal: Circulation (2022)

Introduction: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are independently associated with adverse left (LV) and right (RV) ventricular remodeling. However, the effect of continuous positive airway pressure (CPAP) is unknown. Hypothesis: CPAP prevents adverse remodeling in T2DM+OSA overlap. Methods: In this prospective study, 141 participants (Control: 28; T2DM only: 27; OSA only: 29; T2DM+OSA: 57) were recruited and underwent home sleep testing and cardiac magnetic resonance. Subsequently, 53 adults from the T2DM+OSA group were enrolled in a 3-month, parallel-arm, randomized, placebo-controlled trial comparing active and sham CPAP. The measures of interest were LV and RV remodeling indices (mass/volume). Kruskal-Wallis for multiple groups and Wilcoxon rank-sum and signed-rank tests for paired samples for two groups were applied. Results: Groups were of similar sex [Control (males): 54%; T2DM: 44%; OSA only: 52%; T2DM+OSA: 65%; p=0.31)]; OSA and T2DM+OSA participants were older (age in years: 46± 15; 51±7.8; 53±10; 56±9.1* # ; respectively p=0.001; *p&lt;0.05 vs. control, # p&lt;0.05 vs. T2DM only) and had higher BMI (29.8±6.3; 31±4.8; 34±6.3*; 35.2±6.6* # kg/m 2 , respectively p=0.001). At baseline, LV remodeling index (g/ml) was higher in T2DM+OSA (0.67±0.12; 0.71±0.10; 0.75±0.13; 0.78±0.16*; respectively, p=0.01), whereas RV remodeling index was similar (0.19±0.03; 0.20±0.03; 0.20±0.03; 0.21±0.04; p=0.33). The difference in LV remodeling index persisted after adjustment for age, sex and BMI (p&lt;0.001). CPAP treatment over 3 months prevented progression of adverse LV remodeling compared with sham [difference: CPAP: -0.01 (-0.08, 0.08) g/ml; sham: 0.11 (-0.03, 0.17) g/ml; p=0.03)] but not of RV remodeling index [difference: CPAP: 0.01 (-0.04, 0.08) g/ml; sham: 0.003 (-0.02, 0.04) g/ml; p=0.82)]. Conclusion: T2DM and OSA increased adverse LV but not RV remodeling. CPAP prevented the progression of adverse LV but not RV remodeling.
Abstract 142: Community-wide Bystander-focused Interventions And Sex Disparities In The Receipt Of Bystander Cardiopulmonary Resuscitation In Public
Authors: Audrey L Blewer, Nur Shahidah, Pin Pin Pek, Yih Yng Ng, Colin Tan, Carl Ross de Souza, Wei Ming Ng, Alexander White, Benjamin S Leong, Truls Ostbye, Marcus E Ong
Journal: Circulation (2022)

Introduction: Female sex is associated with lower receipt of bystander cardiopulmonary resuscitation (BCPR) in public. Telephone-assisted CPR (TCPR) may attenuate this known sex difference. It is unknown whether the introduction of community-wide, bystander-focused interventions may reduce this known sex difference and improve outcomes for females. Objectives: We sought to assess whether implementation of bystander-focused, out-of-hospital cardiac arrest (OHCA) interventions attenuated the sex difference seen in receipt of BCPR. We hypothesized that implementation of bystander-focused interventions would reduce the known difference observed in males compared to females in receipt of BCPR in public. Methods: We conducted a retrospective study of adult, non-traumatic OHCAs from the Singapore OHCA registry (1/2011-12/2020). Bystander-focused interventions included TCPR (7/2012 - present), CPR/AED training (04/2014 - present), and myResponder (4/2015 - present). We examined the differences between males vs females in receipt of BCPR in public using descriptive statistics, a sex-intervention interaction term, and hierarchical regression modeling. Results: The registry contained 19,321 events (2011-2020). Excluding pediatric, traumatic, EMS witnessed, and healthcare facility arrests, 18,925 events were analyzed. Of these, mean age was 68±16 and 64% were male. BCPR was administered in 56% of the events, with 61% of males and 54% of females receiving BCPR in public (p-value &lt;0.01). Females had a 29% decreased odds of receiving BCPR compared to males in public (OR: 0.72 (95% CI: 0.58-0.90), p-value &lt;0.01). With inclusion of implementation of bystander-focused interventions as an interaction term with sex, the difference in receipt of BCPR between males and females was no longer observed (p-value: ns). The sex-intervention interaction term was statistically significant (p-value&lt;0.01). No sex differences were observed when modelling survival as an outcome. Conclusion: The introduction of community-wide, bystander-focused interventions may lessen differences seen in receipt of BCPR by males and females in public. Further research on OHCA interventions is needed to increase provision of BCPR and consider addressing this disparity.
Abstract 14748: Genetic and Neurobiological Factors Link Chronic Stress to Earlier Onset Hypertension
Authors: Simran Grewal, Kenechukwu Mezue, Shady Abohashem, Hadil Zureigat, Charbel Gharios, Alexander Cardeiro, Zhaowen Liu, Karmel Choi, Jordan Smoller, Michael Osborne, Ahmed A Tawakol
Journal: Circulation (2022)

Introduction: Chronic stress conditions associate with a greater incidence of hypertension (HTN). Hypothesis: We tested whether genetic risk for or neurobiological features of vulnerability to chronic stress associate with the risk for and timing of HTN. Methods: Data were obtained from Mass General Brigham Biobank participants. HTN was defined as &gt; 2 International Classification of Disease codes at least one week apart. Those with secondary HTN and those diagnosed at age &lt;18 years were excluded. Of this parent dataset, a validated polygenic risk score for neuroticism reflecting stress sensitivity (ssPRS) was assessed in 11,320 participants. Of the same parent dataset, stress-related neural network activity (SNNA), defined as a ratio of amygdalar to regulatory medial prefrontal cortical activity, was measured in 867 individuals who had undergone clinical 18 F-flurodeoxyglucose positron emission tomography imaging. Results: In the genetic subgroup, the median age [interquartile range] of participants was 60 [34-86] years and 56.3% were female. In a Cox regression model, standardized ssPRS predicted incident HTN (hazard ratio [95% confidence interval (CI)]: 1.05 [1.02, 1.08], p&lt;0.001), when adjusted for principal components, age, and sex (Figure 1A). Similarly, standardized SNNA predicted incident HTN (1.44 [1.11, 1.85], p = 0.006) when adjusted for age and sex. The age of onset of HTN was significantly lower in those with high vs. low ssPRS (difference (years) [95% CI]: -1.65 (-2.45, -0.85], p &lt; 0.001) and in those with high vs. low SNNA (-4.67 [-7.68, -1.66], p = 0.002, Figure 1B) in unadjusted models with findings of a similar magnitude and significance in multivariable models. Conclusions: This study identifies genetic and neurobiological factors linking chronic stress to HTN risk and its age of onset. Future studies should evaluate whether therapies targeting this neurobiological pathway may reduce HTN risk.